Effective Method of Lipase-Catalyzed Enantioresolution of 6-Alkylsulfanyl-1,4-dihydropyridines

Abstract

A series of 6-alkylsulfanyl-1,4-dihydropyridines (±)-2 bearing a methoxycarbonylethyl group as a mild easily removable protecting group at S atom have been prepared by alkylation of 6-thioxo-1,4-dihydropyridines 1 with methyl bromopropionate. Candida antarctica lipase B (Novozyme 435 ® , CAL-B) -and Amano Acylase (Aspergillus mellus)-catalyzed kinetic resolution has been investigated in water-saturated diisopropyl ether (IPE) at 25 and 45 C. After acrylic acid methyl ester as leaving group cleavage and alkylation of formed enantioenriched 1,4-dihydropyridine-6-thiolates (-)-4 and (+)-4, optically active 1,4-dihydropyridines (-)-2, (+)-2, (-)-5 and (+)-5 were obtained in 85-99% enantiomeric excess. The experiments present the 6-(methoxycarbonylethyl)sulfanyl group as an essentially new enzymatically labile (activating) group. The ester group being 6 bonds remote from the chiral center undergoes easy enzymatic hydrolysis and could be used for kinetic resolution of racemic 1,4-DHPs. This developed method offers access to mild optically active nucleophilic tiolates, which could be easily derivatized with electrophilic reagents. sodium, potassium or chloride channels and act as selective or multifunctional molecules for the various pharmacobiological activities such as bioprotective, 5 neurotropic, 6 membrane protecting, 7-9 radioprotecting, 10 antidiabetic, 11 gene-transfection, 12 and antibacterial. 13 6-Alkylsulfanyl-1,4-DHPs display cardiovascular, 14-15 hepatoprotective, 16 antioxidant, 17 and antiradical 18 activities (in addition to the above mentioned activities), however, these compounds are still insufficiently studied.Chirality plays an important role in the activity of 1,4-DHPs and both quantitative and qualitative differences between different stereoisomers (enantiomers) have been reported. 19,20 Pharmaceutical evaluations of chiral 1,4-DHPs revealed that their strereoisomers usually have different biological activities. Sometimes the undesired enantiomer caused serious side effects, while in other cases enantiomers were reported to have even the opposite action profile (calcium antagonist -calcium agonist;hypotensive activity -hypertensive activity). 21Chemoenzymatic methods for preparation of chiral drugs have a number of distinct advantages: they are simple, direct, efficient, mild, and cheap in case of multiple (repeated) use of the enzyme. The standard resolution technique, such as incorporation of an enzymatically labile group for the resolution of monocyclic 1,4-DHPs has been in use for the last decade. This approach has been pioneered by groups of Sih 22 and Achiwa, 23 applied to 6-derivatised 1,4-DHPs 24-26 and also used by our research group. [27][28][29][30][31][32] It is worth mentioning that many activating groups applicable to enantioselective lipase-catalyzed kinetic resolution of 1,4-dihydropyridine-3-carboxylates have been screened. An asymmetric 1,4-DHPs alkoxycarbonylmethoxycarbonyl (double esters), 27,28 alkylcarboxymethyloxycarbonyl (reverse esters) in position 5 25,30-33 and acetoxy...

Recent Approaches to Chiral 1,4-Dihydropyridines and their Fused Analogues

“…The enantioselectivity of CAL-B increased together with an increase of the temperature. Thus the best enantioselectivities of CAL-B were achieved at 45°C when the substituent at the position 4 of 1,4-DHP was substituted aryl (Table 3 Enzyme-catalysed kinetic resolution of 6-methoxycarbonylethylsulfanyl-1,4-dihydropyridines rac-4 has been performed by Krauze group using Amano Acylase (Aspergillus mellus) and Candida antarctica lipase B (CAL-B, Novozyme 435 ® ) in wet diisopropyl ether (IPE) with dichloromethane (DCM) as an additive to improve the solubility of the substrate rac-4 [56]. Table 3 shows the most enantioselective examples.…”

“…Enzyme-catalysed kinetic resolution of 6-methoxycarbonylethylsulfanyl-1,4-dihydropyridines rac-4[56].…”

Physical-chemical and in silico Studies of 1,4-dihydropyridine Derivatives

“…For example, nifedipine and amlodipine are included in the World Health Organization (WHO) Model List of Essential Medicines [3]. Derivatives of 1,4-dihydropyridine not only possess properties of calcium channel antagonist and antihypertensive properties [4], but also antiarrhythmic [5], neurotransmitter [6], anticonvulsant [7], antioxidant [8], antiradical [9], anticancer [10], antidiabetic [11], antibacterial [12], cell growth modulator [13], anticoagulant [14], adenosine receptor antagonist [15], multidrug resistance modulator [16] and many other properties [1], [2].…”